tbuckley/cabot-search huggingface dataset:
CTNI-21. TROTABRESIB (CC-90010) IN COMBINATION WITH CONCOMITANT TEMOZOLOMIDE PLUS RADIOTHERAPY AND ADJUVANT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: UPDATED RESULTS FROM A PHASE 1B/2 STUDY
Authors: Maria Vieito, Juan Manuel Sepulveda, Victor Moreno, Filip de Vos, Marjolein Geurts, Elena Lorenzi, Marina Macchini, Martin van den Bent, Gianluca Del Conte, Maria Cruz Martín-Soberón, Petter Brandal, Maria Martinez Garcia, Barbara Amoroso, Tania Sanchez-Perez, Marlene Zuraek, Bishoy Hanna, Ellen Filvaroff, Henry Chang, Marina Arias Parro, Xin Wei, Yu Liu, Zariana Nikolova, Matteo Simonelli
Journal: Neuro-Oncology (2022)

Abstract Trotabresib, a novel bromodomain and extraterminal protein inhibitor, has demonstrated antitumor activity and blood–brain barrier penetration in patients with high-grade gliomas, and enhanced the antiproliferative effects of temozolomide in preclinical models. CC-90010-GBM-002 (NCT04324840) is a phase 1b/2 study investigating the addition of trotabresib to standard-of-care (SOC) concomitant temozolomide plus radiotherapy and adjuvant temozolomide, followed by maintenance trotabresib, in patients with newly diagnosed glioblastoma. The design of the dose escalation (part A) has been described previously (Vieito M, et al. SNO 2021. Abstract CTNI-51). Primary objectives of part A were to establish the safety, tolerability, and maximum tolerated dose/recommended phase 2 dose (RP2D) of trotabresib. In part A, addition of trotabresib to SOC was safe and well tolerated in the concomitant (N = 14) and adjuvant (N = 18) cohorts; the most frequent grade 3/4 treatment-related adverse event was thrombocytopenia (7/14 and 9/18 patients, respectively). The RP2D for trotabresib was 30 mg/day 4 days on/24 days off in both settings. At data cutoff (February 20, 2022), median duration of treatment was 34 weeks (concomitant cohort) and 33 weeks (adjuvant cohort); progression-free survival data are not yet mature. Trotabresib plasma pharmacokinetics and pharmacodynamics were consistent with monotherapy. At last follow-up, 6 and 5 patients remained on treatment in the concomitant and adjuvant dose-escalation cohorts, respectively, including 1 patient in cycle 20 with ongoing complete response. The ongoing randomized phase 2 dose expansion (part B; planned N = 162) is comparing concomitant trotabresib at the RP2D + SOC followed by adjuvant trotabresib at the RP2D + SOC, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off, versus SOC alone in patients with newly diagnosed IDH–wild-type glioblastoma. Key objectives are to compare progression-free and overall survival, safety, and tolerability. Longer follow-up from part A and the first disclosure of data from part B will be presented.
CNSC-35. CANCERS GOT THE NERVE
Authors: Sasi S.Senga
Journal: Neuro-Oncology (2022)

Abstract Brain cancers carry a bleak prognosis despite the increase in our understanding of the disease. Brain tumours are in some ways a distinct entity in comparison to other types of tumours due to the distinct type of cell population in the brain tumour microenvironment. Sympathetic and parasympathetic nervous systems have been shown to exert a context-dependent effect on tumourigenesis. In 2021, I proposed neuronal signalling as a hallmark of cancer, albeit resection of specific nerves to hinder tumourigenesis is both challenging and may not result in the desired outcome. In order to add the nervous system to our armamentarium of therapeutic strategies against cancer, we may need to look beyond conventional methods of reducing synaptic plasticity such as with the use of anti-epileptic drugs. One among the strategy I propose is to utilize epigenetics to our advantage. Using lysine demethylase 5 specifically KDM5C to alter the synapticity in the brain tumour microenvironment is one way of exploiting the synaptic plasticity to our advantage against cancers. Additionally, metabolism intertwines the effects mediated by the nervous system which can be exploited to pivot the tumour-promoting effects of the nervous system towards tumour elimination.
NIMG-103. VOLUMETRIC CHANGES IN GRAY MATTER AFTER RADIOTHERAPY DETECTED WITH LONGITUDINAL MAGNETIC RESONANCE IMAGING IN GLIOMA PATIENTS
Authors: Hye In Lee, Bum-Sup Jang, Min Kyoung Kang, Kihwan Hwang, Chae-Yong Kim, Yu Jung Kim, Koung Jin Suh, Byung Se Choi, Gheeyoung Choe, In Ah Kim
Journal: Neuro-Oncology (2022)

Abstract PURPOSE We evaluated volumetric changes in the gray matter (GM) after radiotherapy (RT) and identified factors that were strongly associated with GM volumetric reduction. METHODS A total of 461 magnetic resonance imagings (MRI) from 105 glioma patients treated with postoperative radiotherapy (RT) was retrospectively analyzed. Study patients’ MRIs were collected at five time points: before RT and 1 month, 6 months, 1 year, and 2 years after RT. Using the ‘FastSurfer’ platform, a deep learning-based neuroimaging pipeline, a total of 73 subsites was automatically segmented from longitudinal MRIs and their volumetric changes were calculated. Each subsite was grouped into 10 functional fields. A multivariable linear mixed-effects model was established to identify the potential predictors of volumetric changes. RESULTS The median volumetric changes in the overall, ipsilateral, and contralateral GM were -3.5%, -4.5%, and -2.4% at 2 years after RT. The functional fields of cognition and execution of movement showed the greatest volumetric reductions. In the multivariable linear mixed model, female and the interaction between age and days after RT were significantly associated with GM volume reduction. The GM volume was significantly reduced in patients older than the subsite-specific threshold age at RT (e.g., 45, 50, and 60 years for hippocampus, Broca area, and Wernicke area, respectively). However, there was no significant GM volumetric reduction in patients younger than the threshold age at RT. CONCLUSIONS GM volumetric changes were identified after RT that could lead to long-term treatment sequelae. Particularly for susceptible patients, individualized treatment and prevention strategies are needed.
PATH-44. VARIANT ALLELIC FREQUENCY OF DRIVER MUTATIONS PREDICTS SUCCESS OF GENOMIC METHYLATION CLASSIFICATION IN CNS TUMORS
Authors: Pouya Jamshidi, Kristyn Galbraith, Matthew Mccord, Lucas Santana-Santos, Lawrence Jennings, Matija Snuderl, Craig Horbinski
Journal: Neuro-Oncology (2022)

Abstract Whole genome CpG DNA methylation profiling is an extremely valuable tool in the workup of central nervous system (CNS) tumors. Reliability of such profiling depends on sufficient tumor cellularity. Many neoplastic entities have well-known driver mutations that occur in virtually 100% of tumor cells, and next-generation sequencing (NGS) assays can detect those mutations and report their relative amounts in the form of Variant Allelic Frequency (VAF). Since NGS and methylation profiling are often done on the same tumor block, we sought to determine whether driver mutation VAF affects the accuracy of methylation profiling, and whether VAF can help establish more rigorous cutoffs for quality assurance. Using NGS and Infinium Epic850K methylation arrays, we evaluated 153 CNS neoplasms representing a range of entities, including TERT promoter-mutant glioblastoma, IDH-mutant astrocytoma, IDH-mutant oligodendroglioma, SHH-driven medulloblastoma, and CTNNB1-driven adamantinomatous craniopharyngioma. VAFs of each driver mutation ranged between 1-60%. One hundred eleven of 153 cases (73%) had a methylation classification score ≥ 0.9, the most widely accepted cutoff for a successful result. A fit-of-mixture analysis via CutoffFinder (PMID: 23251644) suggested that the optimal VAF cutoff=31%, generating an AUC of 0.87. Ninety-six of 107 (89%) cases with a VAF of 31% or higher had a methylation classification score ≥ 0.9, whereas only 15/46 (33%) below 31% were classifiable with methylation profiling (P&amp;lt; 0.0001 by Fisher’s exact test). An independent validation cohort from NYU (N=50) showed nearly identical results, with 37/50 (74%) of cases having a methylation classification score ≥ 0.9, an optimal cutoff=0.32 with an AUC=0.84, and % classification above and below the 0.32 cutoff being 30/34 (88%) and 7/16 (44%), respectively (P=0.002) These data indicate that VAF of driver mutations can serve as a useful predictor of classification success via methylation profiling, and should be taken into account when interpreting methylation profiling results.
BIOM-55. DE RITIS RATIO AS A NOVEL PROGNOSTIC BIOMARKER IN ATYPICAL MENINGIOMAS: A MULTI-INSTITUTIONAL STUDY
Authors: Won Ick Chang, Hwa Kyung Byun, Joo Ho Lee, Chul-Kee Park, In Ah Kim, Chae-Yong Kim, Jong Hee Chang, Seok-Gu Kang, Sang Hyung Lee, Yuki Kuranari, Ryota Tamura, Masahiro Toda, Hong In Yoon, Chan Woo Wee
Journal: Neuro-Oncology (2022)

Abstract PURPOSE To investigate the impact of prognostic serum biomarkers in newly diagnosed surgically resected intracranial atypical meningiomas. METHODS This multi-institutional study included 523 grade 2 (according to the 4th edition of WHO Classification of Tumors of the Central Nervous System) patients who underwent resection between 1998–2018. The baseline characteristics and serum laboratory data within one week after surgery were obtained for analyses investigating the association with progression/recurrence (P/R) rate or progression-free survival (PFS). Optimal cut-offs were calculated for each serum marker using the maxstat package of R. Nomograms were developed based on the multivariate analyses of statistically significant prognosticators. RESULTS Among 523 patients, 454 patients were included in the multivariate analysis for P/R rate excluding patients with incomplete histopathologic or laboratory data. On multivariable analysis, tumor size &amp;gt;5 cm (HR, 2.18; 95% CI, 1.49–3.19) and subtotal resection (HR, 3.60; 95% CI, 2.37-5.47) were associated with higher P/R rate, whereas adjuvant radiotherapy (HR, 0.32; 95% CI, 0.20-0.53) and postoperative platelet &amp;gt;137 x 103/μL (HR, 0.58; 95% CI, 0.39-0.86) were associated with lower P/R rate. Interestingly, postoperative De Ritis Ratio (aspartate aminotransferase/alanine aminotransferase) &amp;gt;2 proved to be an adverse prognosticator (HR, 1.87; 95% CI, 1.15-3.05). Similarly, patients with De Ritis ratio &amp;gt;2 showed inferior PFS (HR, 1.87; 95% CI, 1.23-2.84). In the subgroup of patients who received adjuvant radiotherapy, tumor size &amp;gt;5 cm and postoperative neutrophil-to-lymphocyte ratio &amp;gt;21 were the only prognosticators and were associated with higher P/R rate. On the other hand, postoperative De Ritis ratio &amp;gt;2 remained to be an adverse prognosticator in patients who did not receive radiotherapy. CONCLUSION Postoperative De Ritis Ratio was unrevealed as a novel serum prognosticator in newly diagnosed atypical meningiomas. Further studies are warranted to validate its clinical significance and biological background.
NIMG-70. MAGNETIC RESONANCE HYPOXIA IMAGING FOR RADIATION TREATMENT GUIDANCE IN GLIOBLASTOMA MULTIFORME - A DIAGNOSTIC/PROGNOSTIC CLINICAL IMAGING STUDY
Authors: Caterina Brighi, David Waddington, Paul Keall, Jeremy Booth, Kieran O'Brien, Jonathon Parkinson, Jackie Yim, Dale Bailey, Michael Back, James Drummond
Journal: Neuro-Oncology (2022)

Abstract Local recurrence in glioblastoma (GBM) patients is caused by the ability of tumour cells to develop treatment resistance mechanisms. Hypoxia, which is present in subregions of GBM tumours, is the leading cause of resistance to radiotherapy and is associated with worse clinical outcomes in GBM. Current standard of care treatment does not account for tumour hypoxia. The ability to image tumour hypoxia at various stages of treatment offers opportunities to personalise and improve treatment for GBM patients. Preoperative imaging of tumour hypoxia offers the opportunity for supramarginal resections in surgical planning beyond current neurosurgical standard of care guidelines. Imaging hypoxia prior to radiotherapy enables selective dose escalation strategies to radioresistant tumour regions, increasing the likelihood of local control. Identifying hypoxic tumour regions harbouring progression at follow up is key to intervening at an early stage of tumour recurrence and personalising therapy tailored to the tumour response to treatment. Imaging of tumour hypoxia in routine clinical practice is challenging, as it requires 18FMISO PET, which is not available in most clinical centres. In this clinical imaging study, we aim to investigate the role of oxygen enhanced (OE) and blood-oxygen level dependent (BOLD) MRI as imaging biomarkers of hypoxia in GBM. Aiming to recruit 20 GBM patients, this study involves the addition of OE/BOLD MRI and 18FMISO PET imaging at several timepoints during the course of treatment. The primary objective is to investigate the ability of OE/BOLD MRI to map tumour hypoxia on preoperative scans using 18FMISO PET as the ground truth. Secondary objectives include evaluating the role of hypoxia imaging biomarkers for dose-painting radiotherapy planning and treatment response assessment in GBM. Overall, by validating the role of MRI biomarkers of hypoxia we ought to provide a non-invasive and more accessible means to more effective, personalised treatment to GBM patients.
INNV-26. EMERGENCE OF VIRTUAL TUMOR BOARD [VTB] IN NEURO-ONCOLOGY: OPPORTUNITIES AND CHALLENGES
Authors: Chukwuyem Ekhator, Santosh Kesari, Ramya Tadipatri, Ekokobe Fonkem, Jai Grewal
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. In order to deliver high-quality cancer care, it is necessary to coordinate numerous therapies and providers, and maintain open lines of communication among all professionals involved. Design/ METHODS We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed the records of Genomet, Medical University of South Carolina[MUSC] and Xcures virtual tumor boards. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. RESULTS 30% of VTBs examined launched in 2017. All had a HIPAA compliant online environment. Xcures records reveals median age of female patients was 57yrs and the median age of male patients was 55 years. The data showed that 44% with a confirmed treatment preferred VTB integrated option. 76% of patients in Xcures registry consist of primary CNS tumors. There are at least 556 patients in the tumor registry which included 46% Glioblastoma cases [96% primary, 4% secondary]. MUSC VTB shows 112 thoracic tumor cases and 9 neuro-Oncology cases. Genomet VTB data shows age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infratentorial tumor. Average response time observed in all cases was ≤ 24 hours. CONCLUSION VTBs allow for quicker expert analysis of cases. More studies are needed to gain additional insight into user engagement metrics.
STEM-01. GLIOMA STEM CELLS ACTIVATE PLATELETS BY PLASMA-INDEPENDENT THROMBIN PRODUCTION TO PROMOTE GBM TUMORIGENESIS
Authors: Anthony Sloan, Christine Lee-Poturalski, Harry Hoffman, Peggy Harris, Theresa Elder, Gino Cioffi, Jill Barnholtz-Sloan, Jeremy N Rich, Eckhard Jankowsky, Anirban Sen Gupta, Andrew Sloan
Journal: Neuro-Oncology (2022)

Abstract The interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, for example glioblastoma (GBM) for which metastasis is rare. Histologically, it is known that glioma stem cells (GSCs) are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcome in many cancers. While platelets are known to promote progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Here, we aimed to understand how the bidirectional interaction between platelets and GSCs drives GBM oncogenesis. Male and female NSG mice were transplanted with patient derived GSC lines and treated with antiplatelet and anti-thrombin inhibitors. Immunofluorescence, qPCR, and Western blots were used to determine expression of coagulation mechanism in GBM tissue and subsequent GSC lines. We demonstrate that GSCs co-opt and activate platelets to promote GBM tumor progression. GSCs endogenously produce all coagulation factors of the intrinsic and extrinsic cascade generating thrombin and activating platelets in the absence of plasma. Conversely, inhibition of platelet activation and of thrombin production by GSCs abrogates platelet-mediated GSC self-renewal and growth (p&amp;lt; 0.0005). Similarly, inhibiting intratumoral thrombin production and function decreases tumor formation in vivo (p&amp;lt; 0.005). These studies challenge and revise the longstanding view that the complete coagulation cascades are found only in the liver and plasma demonstrating that cancer stem cells readily execute a highly liver-specific gene expression program that is mechanistically linked to GBM oncogenesis. We show that cancer cells can co-opt non-cancer cells to promote tumor growth, by uncovering the preferential relationship between platelets and GSCs that drive GBM malignancies and identifies a therapeutically targetable novel interaction.
DDEL-17. POOLED CANCER CELL SCREENING IDENTIFIES GENOMIC DETERMINANTS OF NANOPARTICLE DELIVERY TO CANCER CELLS: SUB ANALYSIS OF CENTRAL NERVOUS SYSTEM TUMOR CELL LINES
Authors: Joelle Straehla, Natalie Boehnke, Hannah Safford, Mustafa Kocak, Matthew Rees, Melissa Ronan, Danny Rosenberg, Jaime Cheah, Jennifer Roth, Angela Koehler, Paula Hammond
Journal: Neuro-Oncology (2022)

Abstract Background There is great interest in utilizing nanoparticles to improve drug delivery to central nervous system (CNS) tumors, but the biologic features underlying successful delivery at the tumor site are not known. METHODS We developed a pooled screening assay to investigate cellular features predictive of nanoparticle delivery and screened 35 fluorescent nanoparticle formulations against 488 pooled cancer cell lines with DNA barcodes. The nanoparticle library was comprised of nonlethal liposomal or polymeric cores with varied surface functionality, including natural and synthetic polymers. Cells were profiled using fluorescence-activated cell sorting and barcodes sequenced and deconvolved to generate an association score for each nanoparticle-cell line pair. RESULTS Of 488 cancer cell lines, 22 cancer cell lineages (tissues of origin) were included. There were 35 cell lines derived from CNS tumors; of these 22 were classified as astrocytoma or glioblastoma, one as oligodendroglioma, and 2 as medulloblastoma. Of CNS tumor cell lines, 40% were from female patients and average age at cell line derivation was 52 years; TP53 hotspot mutations were detected in 25/35 lines, PTEN hotspot mutations in 15/25 lines. Using unsupervised hierarchical clustering by nanoparticle association profiles, CNS tumor lines did not cluster together by lineage, subtype, or mutation status but rather by baseline expression of genes involved in nanocarrier trafficking. Nanoparticle association profiles were heterogeneous among the CNS tumor lines for most formulations, though CNS tumor lines had high association with polystyrene formulations with respect to other lineages. Select CNS tumor lines had high uptake of liposomes coated with the natural polymers fucoidan, alginate, hyaluronic acid and chondroitin sulfate; these trends were further probed in a non-pooled screen of 5 additional cell lines. Conclusions Uptake of liposomal and polymeric nanoparticles is heterogeneous across CNS tumor lines, but can be predicted using baseline gene expression.
QLTI-09. DEFINING GLOBAL BENCHMARK OUTCOMES FOR TRANSSPHENOIDAL SURGERY OF PITUITARY ADENOMAS: A MULTICENTER ANALYSIS OF 2862 CASES
Authors: Richard Drexler, Roman Rotermund, Timothy Smith, John Kilgallon, Jürgen Honegger, Isabella Nasi-Kordhishti, Paul Gardner, Zachary Gersey, Hussein Abdallah, John Jane, Alexandria Marino, Ulrich Knappe, Nesrin Uksul, Jamil Rzaev, Evgeniy Galushko, Ekaterina Gormolysova, Anatoliy Bervitskiy, Henry Schroeder, Márton Eördögh, Marco Losa, Pietro Mortini, Rüdiger Gerlach, Mohammed Azab, Karol Budohoski, Robert Rennert, Michael Karsy, William Couldwell, Apio Antunes, Jörg Flitsch, Franz Ricklefs
Journal: Neuro-Oncology (2022)

Abstract Benchmarks are important to measure and aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery are not available. Therefore, we aimed to establish robust, standardized outcome benchmarks for transsphenoidal surgery of pituitary adenomas. A total of 2862 transsphenoidal tumor resections from 12 high-volume centers in 4 continents were analyzed. Patients were risk stratified and the median values of each center’s outcomes were established. The outcome benchmark was defined as the 75th percentile of all median values for a particular outcome as defined by Staiger et al. Out of 2862 patients, 1201 (41.9%) defined the benchmark cohort. The proportion of benchmark cases contributing to the final cohort ranged across centers between 22.1% to 59.7%. Within the benchmark cases, 928 (73.3%) patients underwent microscopic (MTS) and 263 (21.9%) patients endoscopic endonasal resection (EES). The overall postoperative complication rate was 18.9% with an in-hospital mortality between 0.0-0.8%. Benchmark cutoffs were ≤ 3.3% for reoperation rate, ≤ 4.6% for cerebrospinal fluid leak requiring intervention, and ≤ 15.3% for transient diabetes insipidus. At 6 months follow-up, benchmark cutoffs were calculated as follows: readmission rate: ≤ 7.1%, new hypopituitarism ≤ 15.5%, new neurological deficit ≤ 1.2%, tumor remnant ≤ 25.5%. This analysis defines benchmark values for transsphenoidal resection of pituitary adenomas targeting morbidity, mortality, surgical and tumor-related outcomes. The benchmark cutoffs can be used to assess different centers, patients’ populations, and novel surgical techniques.